Contrasting genetic effects within STAT4 define susceptibility and protection in Leishmania guyanensis Cutaneous Leishmaniasis

Lener Santos da Silva; Josué Lacerda de Souza; Lizandra Stephanny Fernandes Menescal; Júlia da Costa Torres; Ana Vitoria Sena Gouveia; Eryck Gabriel Rodrigues Silva; Micael Davi Lima de Oliveira; Marcus Vinitius de Farias Guerra; Mauricio Morishi Ogusku; Landry Erick Mombo; Antônio Luiz Boechat; Jose Pereira de Moura Neto; Pritesh Lalwani; Aya Sadahiro; Rajendranath Ramasawmy

doi:10.1093/infdis/jiag175

Contrasting genetic effects within STAT4 define susceptibility and protection in Leishmania guyanensis Cutaneous Leishmaniasis

J Infect Dis. 2026 Mar 30:jiag175. doi: 10.1093/infdis/jiag175. Online ahead of print.

Authors

Lener Santos da Silva^{1

2}, Josué Lacerda de Souza^{1

2}, Lizandra Stephanny Fernandes Menescal³, Júlia da Costa Torres³, Ana Vitoria Sena Gouveia², Eryck Gabriel Rodrigues Silva³, Micael Davi Lima de Oliveira³, Marcus Vinitius de Farias Guerra⁴, Mauricio Morishi Ogusku⁵, Landry Erick Mombo⁶, Antônio Luiz Boechat³, Jose Pereira de Moura Neto³, Pritesh Lalwani^{3

7}, Aya Sadahiro³, Rajendranath Ramasawmy^{1

2

3

4}

Affiliations

¹ Programa de Pós-Graduação em Biodiversidade e Biotecnologia da Amazonia Legal (Rede Bionorte), Universidade do Estado do Amazonas, Manaus, Brazil.
² Faculdade de Medicina, Universidade Nilton Lins, Manaus, Amazonas, Brazil.
³ Programa de Pós-Graduação em Imunologia Básica e Aplicada, Universidade Federal do Amazonas, Manaus, Amazonas, Brazil.
⁴ Fundação de Medicina Tropical Doutor Heitor Vieira Dourado, Manaus, Brazil.
⁵ Laboratório de Micobacteriologia, Instituto Nacional de Pesquisas da Amazônia, Manaus, Amazonas, Brazil.
⁶ Laboratory of Molecular and Cellular Biology, University of Science and Technology of Masuku (USTM), Franceville, Gabon.
⁷ Laboratory of infectious diseases, Instituto Leônidas e Maria Deane (ILMD)/FIOCRUZ Amazônia, Manaus, Amazonas, Brazil.

PMID: 41905779
DOI: 10.1093/infdis/jiag175

Abstract

Background: Leishmania guyanensis-associated cutaneous leishmaniasis (Lg-CL) is endemic in the Brazilian Amazonas. Despite similar exposure to the pathogen in endemic areas, only a subset of individuals develops disease, suggesting host-genetic control. STAT4 triggers IL-12-dependent Th1 differentiation and IFN-γ production, essential for macrophage-mediated parasite clearance.

Methods: We performed a case-control study of 802 Lg-CL patients and 842 endemic controls (ECs). Eleven STAT4 variants (10 SNVs and one insertion/deletion) were genotyped. Associations were assessed using logistic regression adjusted for age and sex across multiple genetic models, with haplotype analysis adjusted for age and sex via omnibus and likelihood ratio tests.

Results: Two SNVs exerted contrasting associations: the rs1031509 T allele increased susceptibility (ORadj=1.5 [95% CI 1.3-1.7], Padj-B= 1.3x10-5), while the rs6434435 A allele conferred protection (ORadj=0.56 [95%CI 0.43- 0.68], Padj-B=2.6x10-8). Omnibus haplotype analysis revealed significant global differences in haplotype distribution between Lg-CL and ECs (Omnibus unadjusted χ² = 55.65, df = 13, P = 3.11×10⁻7, likelihood ratio test χ² = 67.81, df = 13, P = 2.02×10⁻9), with a specific high-risk combination (AIGAAAGCTGC) associated with a nine-fold increase in susceptibility (adjusted OR = 9.12 [95%CI 4.22-19.70], P=1.9×10⁻8; FDR q=2.4×10⁻7). Genotype-cytokines analyses revealed that carriers of the protected rs6434435 A allele had significantly higher TNF-α plasma levels under dominant model (+40.2%, FDR adjusted P = 0.026) and additive model, with a nominal trend toward elevated IFN-γ.

Conclusions: Haplotypic variation at this locus significantly shapes host inflammatory responses, highlighting STAT4 as a key immunogenetic determinant of resistance to Leishmania infection.

Keywords: Leishmania guyanensis; Cutaneous leishmaniasis; Haplotype analysis; Host genetic susceptibility; STAT4.

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